The alpha-subunit of the glycoprotein hormones is normally expressed in pituitary thyrotropes and gonadotropes, and in placental cells. A major advance in the understanding of alpha- subunit expression in pituitary cells resulted from recent studies in transgenic mice that revealed the presence of a powerful enhancer region about 4,000 base pairs upstream of the transcriptional start-site. Of considerable interest, this upstream regulatory area plays an important role in targeting alpha-subunit gene expression to the correct pituitary cell lineages, and exhibits a dual role as stimulatory in alpha- expressing cells and inhibitory in non-alpha-expressing cells, such as GH3 somatolactotropes. Most importantly, these investigations document strong interactions between the distal enhancer and specific areas on the proximal promoter, suggesting not only protein-DNA but also novel protein-protein interactions. The major focus of this competing renewal is to extend these investigations and systematically study the pivotal roles of this upstream regulatory area, leading to the identification of the key cellular proteins that functionally interact with that area. In addition, the studies will demonstrate the physiological consequences of disrupting the function of this area in transgenic mice. These approaches will utilize the most modern techniques of molecular and cell biology incorporated into cell culture and transgenic technology. These studies will provide new fundamental knowledge that will impact our understanding of physiological and pathological pituitary alpha-subunit expression.